U.S. Pat. No. 5,143,916 and divisionals thereof describe (1-naphthyl)-4-alkylpipcrazine compounds disclosed as 5-HT1A receptor agonist and antagonist ligands that decrease arterial blood pressure and heart rate.
ES 2027898 describes (2-methoxyphenyl)piperazine derivatives with 5-HT1A receptor activity which are secondary amide and secondary amine derivatives.
In accordance with this invention are provided novel piperazine ethylamide derivatives which are agonists and antagonists of the 5HT1A receptor subtype. By virtue of their high binding affinity to the 5HT1A receptor, compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, obsessive-compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer""s disease, Parkinson""s disease, obesity and migraine.
Compounds of the present invention are represented by the general formula (1), 
in which:
R1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
R2 is cycloalkyl, alkyl or N(R4R5);
R3 is aryl or heteroaryl;
R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl, or taken together R4 and
R5 form a heterocycloalkyl; provided that R4 and R5 are not both hydrogen;
A is (CH2)m;
m is an integer from 1 to 4; and
n is an integer from 1 to 3; or a pharmaceutical salt thereof.
In preferred embodiments of the present invention, R1 is aryl, R2 is cycloalkyl and R3 is phenyl.
xe2x80x9cAlkylxe2x80x9d as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably 1 to 3 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
xe2x80x9cAlkoxyxe2x80x9d as used herein means an alkyl-O group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
xe2x80x9cArylxe2x80x9d as used herein means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary aryl groups include phenyl and naphthyl. In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. The aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
xe2x80x9cCycloalkylxe2x80x9d as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
xe2x80x9cHeterocycloalkylxe2x80x9d as used herein means a monocyclic alkyl group having from 3 to 8 members including from 1 to 3 heteroatoms selected from N, O and S. In some preferred embodiments heterocycloalkyl may be substituted with 1 to 3 substituents.
Halogen, as used herein means fluorine, chlorine, iodine and bromine.
xe2x80x9cHeteroarylxe2x80x9d means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and benzodioxanyl. Preferred heteroaryl groups include thienyl, pyridyl, pyrimidinyl, indolyl, and benzodioxanyl. More preferred are heteroaryl groups including 3-thienyl, 2-pyridyl, 2-pyrimidinyl, indol-4-yl and benzodioxan-5-yl. The heteroaryl group may be substituted with one or more substituents. Substituted heteroaryl groups preferably have from 1 to 3 substituents.
Suitable substituents include, unless otherwise noted, halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl means an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing conventional methods which utilize readily available reagents and starting materials. For example, reaction of known arylpiperazines (A) with chloroacetonitrile and subsequent reduction with lithium aluminum hydride provides known and novel (4-aryl)piperazine-1-ethylamine derivatives (B). Treatment with acid chlorides provides the subsequent amide (C), which can be reduced to the amine (D) by the action of a reducing agents such as lithium aluminum hydride or borane. The amine (D) may then be again acylated to provide the required compounds (1) of the present invention. 